It is known that radionuclidically labeled particulate material of a sufficient size (10 .mu. m diameter) administered into the afferent blood supply of a given organ will lodge in the capillary bed of that organ. When such particulate material has been uniformly mixed with the blood afferent to the organ prior to reaching the capillary bed, the distribution of the radionuclide in the organ reflects the capillary blood flow to that organ. Thus, radionuclidically labeled particulate materials have been successfully used in scintigraphic evaluation or perfusion abnormalities of the lungs and other tissues such as occur in infarction and various types of vascular occlusion with or without infarction.
Macroaggregated human serum albumin labeled with iodine-131 has been widely used for the above described purposes. However, radionuclides such as technetium-99m are preferred over iodine-131 in scintigraphic studies because of their lower radiation dose and greater compatibility of their gamma emission with existing radiation detection devices. One procedure described in the literature for the preparation of technetium-99m-labeled macroaggregated human serum albumin comprises initially labeling unaggregated human serum albumin with technetium-99m using either Fe(III) and ascorbic acid, or Sn(II) followed by heat denaturation and macroaggregation of the technetium-99m-labeled albumin. Such procedures require the availability of skilled radiopharmacists at the site of use of the preparation to prepare the material prior to use. Moreover, the short physical half-life of the technetium-99m does not allow sufficient time to completely qualify the product prior to use. Such qualification includes assessment of particle size distribution, particle density, degree of binding of the technetium-99m to the particles, in vivo distribution pattern of the labeled particles in test animals, and determination of apyrogenicity, sterility and general safety of the product. Moreover, in preparations in which the human serum albumin is labeled with technetium-99m prior to its macroaggregation, there is a tendency for the technetium-99m label to come off or elute from the product thereby yielding undesirable unbound activity. An approach to the solution of this problem in the past has been to react heat denatured albumin microspheres with technetium-99m using Fe(II) and ascorbic acid. Such techniques are time consuming and require special apparatus. The tendency for technetium-99m to elute from such products remains a significant factor, such that the free technetium-99m must be washed from the labeled product shortly before administration thereof to the patient.
An additional method of formulating technetium-99m into a preparation suitable for the scintigraphic evaluation of perfusion abnormalties known in the art comprises binding the technetium-99m in inorganic precipitates of iron or tin. Such inorganic precipitates suffer from a lack of precise definition of particle size distribution as the particle size will vary as a function of concentration of ingredients and passage of time after preparation. Generally, the higher the concentration of ingredients and the longer the time after preparation the larger is the mean particle size. Moreover, long-term retention of the inorganic precipitate in the lung has been demonstrated for certain such preparations, suggesting the possibility of undesirable long-term toxicity.
In accordance with the present invention, a preparation for studying capillary perfusion of tissues is provided which is free of the disadvantages of prior art preparations noted above. Thus, preparations of the present invention can be completely qualified prior to distribution because they are stable for well over 6 months at room temperature or under refrigeration. The stable preparations of the present invention are further characterized by being amenable to virtual quantitative labeling with technetium-99m by mixing therewith without the need of washing or other preparative procedures. The technetium-99m is firmly bound and does not usually elute from the particles of the preparations of the invention for over 24 hours after labeling.